Water-soluble mono-betaine hydrazones of the aminochromes and process of preparing same



Patented Oct. 13, 1953 UNITED STATES PATENT OFFICE WATER-SOLUBLE MON O-BETAINE HYDRA- ZONES OF THE AMINOCHROMES AND PROCESS OF PREPARING SAME Harry Sobotka, New York, N. Y., assignor to Mount Sinai Hospital Research Foundation, Inc., New York, N. Y., a membership corporation of New York No Drawing. Application October 19, 1949, Serial No. 122,357

8 Claims. (01. 260-319) 2 This invention relates to water-soluble derivathe solution. On the other hand, their solution tives of aminochromes and to a process for preor suspension in fatty oils or propylene glycol is paring the same. unsuitable for therapeutic usage.

The term aminochromes as used herein is in- Adrenochrome derivatives having increased tended to designate certain oxidation products of 5 stability have been prepared by reacting adrenoa-dihydroxyphenyl-e-alkylamino alkanes, and chrome with various nitrogenous keto-agents, more particularly the orthoquinones of the dihysuch as hydroxylamine, semicarbazide and subdroindoles. Oxidation of these compounds by stituted hydrazines. (Belgium Patent No. 453,- bromine, iodates, silver oxide and also by specific 374.) However, the resulting oximes, semicaroxidases of the tyrosinase type, leads to the forbazones and hydrazones are but slightly soluble mation of dark-red or purple oxidation products in water at normal or body temperature, their which have been formulated as orthoquinones of solubility not exceeding 005 percent or one part dihydroinololes, the carbonyl groups being prein 2000. sumably in positions 5 and 6: I have prepared highly water-soluble deriva- H 5 tives of the aminochromes which are stable and injectable in neutral sterile aqueous solution.

B, More particularly, I have found that the aminochromes form extremely water-soluble and stable N compounds with hydrazides of acetic acid carrying a quaternary nitrogen atom such as trimethylacethydrazide ammonium chloride. These hydrazides may be properly referred to as betaine hydrazides. The resulting condensation products (betaine hydrazones) dissolve in water, physio- 5 logical saline or phosphate buffer solutions in a proportion of up to 20 percent. These solutions,

wherein R1 maybe an alkyl group such as methyl, ethyl or isopropyl; R2 may be H or the methyl group; and R3 may be H or OH. An alternative formulation as paraquinoid betaine or zwitterion has also been proposed:

adjusted to pH 6-7.5, and after passage through Re a sterile filter show no decomposition or discoloration after standing for six months at 4 0. They have been injected intravenously and intramuscu" H larly in quantities up to 500 mg into dogs with- R1 out any toxic effects except for symptoms due to When using bromine or iodate as the oxidizing their acute effect on the blood pressure. agent, halogen substitution also occurs on carbon Betaine hydrazides of the type used in preparatom 2 in the heterocycle. The earliest known ing the betaine hydra'zones of the present invenrepresentative of the aminochromes has been tion have been used as a chemical tool in the isodesignated adrenochrome, obtainable from adrenlation of ketonic hormone compounds with which alin; similarly, the corresponding cyclized oxithey form transient, easily dissociated intermedidation product of epinine may be designated as ates (Girard and Sandulesco, U. S. Patent No. epinochrome, of aludrine as aludrinochrome, 40 2,045,132), but so far as I am aware have never etc. heretofore been used in forming water soluble Several pharmacological effects have been obcondensation products sufficiently stable to warserved with, or ascribed to, adrenochrome and its rant consideration for pharmaceutical purposes.

analogs. It has been found that the injection of e The synthesis of the new compounds of the 10-20 mg. of halogenoadrenochrome, repeated present invention is described in the following exonce or twice, into experimentally hypertensive amples:

animals exerts a strong and protracted anti- Example I.Trimethylacethydmeone ammonium pressor efifect, i. e., it produces a lowering of the chloride of L-adrenochrome arterial blood pressure to normal levels for a pe- I H riod of several weeks. Amounts of 1.0 mg. and T less have been shown to shorten the bleedin time (CH3) CH2 0 O NE A S in experimental animals and man, an effect desig- (71 nated as hemcstatic. r H

However, aminochromes are in general only E slightly soluble in water, physiological saline and I other aqueous solutions. Moreover, such dilute 3.8 2 -ad enochrome were disaqueous solutions are very unstable and betray solved in cc. absolute methanol containing 1% the decomposition of the active principle by disglacial acetic acid and 3-6 a. (6.022 mol.) tricoloration and melanization at room temperamethylacethyrazide ammonium chloride were tu within a f w minutes after preparation of added and the solution refluxed for 15 minutes.

The color changed from red to orange-brown indicating the progress of the condensation reaction. To the cooled solution was added 300 cc. icecold absolute ether. The oily derivative which crystallized on standing was redissolved in 200 cc. dry methanol and purified by shaking with or chromatographing on aluminum oxide of slightly acid reaction. The orange-red supernatant (or eluate), when concentrated in vacuo under nitrogen, yields the trimethyl acetylhydrazone-ammonium chloride of L-adrenochrome in a yield of 6.5 g. The substance consists of cinnabar-red crystals, melting under decomposition at 150 C. On elementary analysis, it shows the composition demanded by the formula Adrenochrome when given the presently preferred paraquinoid betaine or "zwitterion formulation may be represented by the following structural formula:

H Q on Emmple II. Trimethylacethydrazone ammonium chloride of epinochrome Epinochrome was prepared from epinine (desoxyepinephrine) hydrochloride by oxidation with silver oxide in absolute methanol containing 2% formic acid. 3.3 g. epinochrome was condensed with trimethylacethydrazide ammonium chloride under the conditions of Example I. The resulting product consists of red crystals melting under decomposition at 140 C. Epinochrome may be represented by the following structural formula E o- H H Example III.-Trimethylacethydrazone ammonium chloride of DL-aludrinochrome The N-isopropyl homolog of DL-epinephrine, commercially known as Aludrine or Isuprel, was oxidized in a mixture of 4 parts methanol and 6 parts isopropanol with silver oxide to l-isopropyl- 3-hydroxy-5,6-dil etotetrahydroindole (aludrinochrome). This purplish-red crystalline compound was condensed in the manner described previously with trimethylacethydrazide ammonium chloride to yield a reddish-brown hydrazone melting under decomposition of 195 C. Aludrinochrome may be represented by the following structural formula:

Instead of carrying on the condensation of the aminochrome after this compound has been isolated in solid form, the condensation may be carried out directly in the acetic methanol solution of the respective aminochrome. If this is done, the resulting hydrazone will require further purification by recrystallization.

It will be understood that the specific aminochromes mentioned above are cited by way of example only, and that the process may be carried on with the use of any of the orthoquinones of the dihydroindoles having the structural formula:

H o R, R1 0* i/ wherein R1 may be ethyl, or isopropyl;

wherein R4, R5 and Rs represented three alkyl groups individually attached to the quaternary nitrogen atom, and X is a monovalent anion such as Cl, Br-, HSOr or OH-.

In its broader aspects the invention may be defined as including any of the aminochrome derivatives falling within the formula:

Ri-Rs and X having the meanings set forth above.

I claim: 1. The process of producing water-soluble trialkyl mono-betaine hydrazones of aminochromes conformin to the formula:

wherein R1 is selected from the group consisting of methyl, ethyl and isopropyl radicals; R2 is selected from the group consisting of hydrogen and the methyl radical; R3 is selected from the group consisting of hydrogen and the hydroxy radical; R4, R and R6 represent alkyl groups, and X is a monovalent anion, which comprises reacting an orthoquinone of a dihydroindole having the formula:

with an acethydrazide having the formula:

the symbols R1; R2, R3, R4, R5, R6 and X used in defining the formulas for the orthoquinone and the acethydrazide having the same meaning as set forth in defining the reaction product.

2. The process of producing trimethyl acethydrazone ammonium chloride of adrenochrome conforming to the formula:

H (CHzOaN-CHr-C O-NH-N oH I H 01 O which comprises reactin adrenochrome having the formula H O OH with trimethyl acethydrazide ammonium chloride having the formula:

CH3 CHz-C0NHNH1 H3 CI 3. The process of preparing trimethyl acethydrazone ammonium chloride of epinochrome havwith trimethyl ride having the 'acethydrazide ammonium chloformula CHaN-OHlC O-NH-NH:

4. The process of producing trimethyl acethydrazone ammonium chloride of aludrinochrome having the structural formula:

which comprises reacting aludrinochrome having the formula:

with trimethyl acethydrazide ammonium chloride having the formula CHaN-CHzC ONHNH 5. A water-soluble aminochrome derivative conforming to the formula:

wherein R1 is selected from the group consisting of the methyl, ethyl and isopropyl radicals; R2 is selected from the group consisting of hydrogen and the methyl radical; R3 is selected from the group consisting of hydrogen and the hydroxy radical; R4, R5 and R6 represent alkyl groups, and X is a monovalent anion.

6. The trimethyl acethydrazone ammonium chloride of adrenochrome having the structural formula:

7. The trimethyl acethydrazone ammonium chloride of epinochrome having the structural formula:

8. The trimethyl acethydrazone ammonium chloride of aludrinochrome having the structural formula:

HARRY SOBOTKA.

No references cited. 

1. THE PROCESS OF PRODUCING WATER-SOLUBLE TRIALKYL MONO-BETAINE HYDRAZONES OF AMINOCHROMES CONFORMING TO THE FORMULA: 